Identification of Four Mouse Diabetes Candidate Genes Altering β-Cell Proliferation
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{"title"=>"Identification of Four Mouse Diabetes Candidate Genes Altering β-Cell Proliferation", "type"=>"journal", "authors"=>[{"first_name"=>"Oliver", "last_name"=>"Kluth", "scopus_author_id"=>"35361900200"}, {"first_name"=>"Daniela", "last_name"=>"Matzke", "scopus_author_id"=>"55543500800"}, {"first_name"=>"Anne", "last_name"=>"Kamitz", "scopus_author_id"=>"54998005800"}, {"first_name"=>"Markus", "last_name"=>"Jähnert", "scopus_author_id"=>"55892264800"}, {"first_name"=>"Heike", "last_name"=>"Vogel", "scopus_author_id"=>"37044712000"}, {"first_name"=>"Stephan", "last_name"=>"Scherneck", "scopus_author_id"=>"24391456700"}, {"first_name"=>"Matthias", "last_name"=>"Schulze", "scopus_author_id"=>"7103093978"}, {"first_name"=>"Harald", "last_name"=>"Staiger", "scopus_author_id"=>"6603742406"}, {"first_name"=>"Fausto", "last_name"=>"Machicao", "scopus_author_id"=>"26643593000"}, {"first_name"=>"Hans Ulrich", "last_name"=>"Häring", "scopus_author_id"=>"36038728300"}, {"first_name"=>"Hans Georg", "last_name"=>"Joost", "scopus_author_id"=>"7006623452"}, {"first_name"=>"Annette", "last_name"=>"Schürmann", "scopus_author_id"=>"7006838607"}], "year"=>2015, "source"=>"PLoS Genetics", "identifiers"=>{"issn"=>"15537404", "scopus"=>"2-s2.0-84943542650", "pmid"=>"26348837", "doi"=>"10.1371/journal.pgen.1005506", "pui"=>"606367826", "isbn"=>"1553-7390", "sgr"=>"84943542650"}, "id"=>"21558eb4-fe1e-30df-8056-daf95b0aff83", "abstract"=>"Beta-cell apoptosis and failure to induce beta-cell regeneration are hallmarks of type 2-like diabetes in mouse models. Here we show that islets from obese, diabetes-susceptible New Zealand Obese (NZO) mice, in contrast to diabetes-resistant C57BL/6J (B6)-ob/ob mice, do not proliferate in response to an in-vivo glucose challenge but lose their beta-cells. Genome-wide RNAseq based transcriptomics indicated an induction of 22 cell cycle-associated genes in B6-ob/ob islets that did not respond in NZO islets. Of all genes differentially expressed in islets of the two strains, seven mapped to the diabesity QTL Nob3, and were hypomorphic in either NZO (Lefty1, Apoa2, Pcp4l1, Mndal, Slamf7, Pydc3) or B6 (Ifi202b). Adenoviral overexpression of Lefty1, Apoa2, and Pcp4l1 in primary islet cells increased proliferation, whereas overexpression of Ifi202b suppressed it. We conclude that the identified genes in synergy with obesity and insulin resistance participate in adaptive islet hyperplasia and prevention from severe diabetes in B6-ob/ob mice.", "link"=>"http://www.mendeley.com/research/identification-four-mouse-diabetes-candidate-genes-altering-%CE%B2cell-proliferation", "reader_count"=>23, "reader_count_by_academic_status"=>{"Unspecified"=>1, "Researcher"=>6, "Student > Ph. D. Student"=>7, "Student > Master"=>5, "Other"=>3, "Student > Bachelor"=>1}, "reader_count_by_user_role"=>{"Unspecified"=>1, "Researcher"=>6, "Student > Ph. D. Student"=>7, "Student > Master"=>5, "Other"=>3, "Student > Bachelor"=>1}, "reader_count_by_subject_area"=>{"Unspecified"=>1, "Biochemistry, Genetics and Molecular Biology"=>5, "Agricultural and Biological Sciences"=>12, "Medicine and Dentistry"=>2, "Pharmacology, Toxicology and Pharmaceutical Science"=>2, "Computer Science"=>1}, "reader_count_by_subdiscipline"=>{"Medicine and Dentistry"=>{"Medicine and Dentistry"=>2}, "Agricultural and Biological Sciences"=>{"Agricultural and Biological Sciences"=>12}, "Computer Science"=>{"Computer Science"=>1}, "Biochemistry, Genetics and Molecular Biology"=>{"Biochemistry, Genetics and Molecular Biology"=>5}, "Unspecified"=>{"Unspecified"=>1}, "Pharmacology, Toxicology and Pharmaceutical Science"=>{"Pharmacology, Toxicology and Pharmaceutical Science"=>2}}, "reader_count_by_country"=>{"Croatia"=>1}, "group_count"=>0}

Scopus | Further Information

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Figshare

  • {"files"=>["https://ndownloader.figshare.com/files/2255161"], "description"=>"<p>(A) Representative pictures of total pancreas slices from NZO and B6-ob/ob mice stained for insulin (digital red-colouring) before carbohydrate feeding (-CH) at day 0 and after 32 days of carbohydrate (+CH) feeding (upper panel). Morphometric analysis of insulin staining from 3–5 animals per time point performed in 3 cutting planes with regard to islet size (left panel), islet number per slice (middle panel), and islet area as percentage of total pancreatic area (right panel). Data are mean ± s.e.m.; *<i>P</i>≤0.05 (lower panel). (B) Representative immunohistochemical staining of Ki-67 in pancreatic slices from B6-ob/ob and NZO mice at the indicated time points of carbohydrate-free (-CH) or carbohydrate (+CH) feeding (upper panel). Quantification of Ki-67 positive islet cells from B6-ob/ob and NZO mice fed-CH or +CH at the indicated time points. Data represent mean ± s.e.m. of 4–6 animals, calculated from mean values of 3 cutting planes per pancreas; *<i>P</i><0.05 (lower panel).</p>", "links"=>[], "tags"=>["adaptive islet hyperplasia", "Ifi 202b Adenoviral overexpression", "NZO islets", "B 6", "57BL", "Mouse models", "Insulin resistance", "Pcp 4l", "Ifi 202b", "qtl", "genes differentially", "islet cells"], "article_id"=>1537229, "categories"=>["Uncategorised"], "users"=>["Oliver Kluth", "Daniela Matzke", "Anne Kamitz", "Markus Jähnert", "Heike Vogel", "Stephan Scherneck", "Matthias Schulze", "Harald Staiger", "Fausto Machicao", "Hans-Ulrich Häring", "Hans-Georg Joost", "Annette Schürmann"], "doi"=>"https://dx.doi.org/10.1371/journal.pgen.1005506.g001", "stats"=>{"downloads"=>7, "page_views"=>43, "likes"=>0}, "figshare_url"=>"https://figshare.com/articles/_Diabetes_resistance_of_B6_ob_ob_mice_is_conferred_by_an_adaptive_islet_hyperplasia_/1537229", "title"=>"Diabetes resistance of B6-ob/ob mice is conferred by an adaptive islet hyperplasia.", "pos_in_sequence"=>0, "defined_type"=>1, "published_date"=>"2015-09-08 03:19:38"}
  • {"files"=>["https://ndownloader.figshare.com/files/2255169", "https://ndownloader.figshare.com/files/2255170", "https://ndownloader.figshare.com/files/2255171", "https://ndownloader.figshare.com/files/2255172"], "description"=>"<div><p>Beta-cell apoptosis and failure to induce beta-cell regeneration are hallmarks of type 2-like diabetes in mouse models. Here we show that islets from obese, diabetes-susceptible New Zealand Obese (NZO) mice, in contrast to diabetes-resistant C57BL/6J (B6)-ob/ob mice, do not proliferate in response to an in-vivo glucose challenge but lose their beta-cells. Genome-wide RNAseq based transcriptomics indicated an induction of 22 cell cycle-associated genes in B6-ob/ob islets that did not respond in NZO islets. Of all genes differentially expressed in islets of the two strains, seven mapped to the diabesity QTL <i>Nob3</i>, and were hypomorphic in either NZO (<i>Lefty1</i>, <i>Apoa2</i>, <i>Pcp4l1</i>, <i>Mndal</i>, <i>Slamf7</i>, <i>Pydc3</i>) or B6 (<i>Ifi202b</i>). Adenoviral overexpression of <i>Lefty1</i>, <i>Apoa2</i>, and <i>Pcp4l1</i> in primary islet cells increased proliferation, whereas overexpression of <i>Ifi202b</i> suppressed it. We conclude that the identified genes in synergy with obesity and insulin resistance participate in adaptive islet hyperplasia and prevention from severe diabetes in B6-ob/ob mice.</p></div>", "links"=>[], "tags"=>["adaptive islet hyperplasia", "Ifi 202b Adenoviral overexpression", "NZO islets", "B 6", "57BL", "Mouse models", "Insulin resistance", "Pcp 4l", "Ifi 202b", "qtl", "genes differentially", "islet cells"], "article_id"=>1537237, "categories"=>["Uncategorised"], "users"=>["Oliver Kluth", "Daniela Matzke", "Anne Kamitz", "Markus Jähnert", "Heike Vogel", "Stephan Scherneck", "Matthias Schulze", "Harald Staiger", "Fausto Machicao", "Hans-Ulrich Häring", "Hans-Georg Joost", "Annette Schürmann"], "doi"=>["https://dx.doi.org/10.1371/journal.pgen.1005506.s001", "https://dx.doi.org/10.1371/journal.pgen.1005506.s002", "https://dx.doi.org/10.1371/journal.pgen.1005506.s003", "https://dx.doi.org/10.1371/journal.pgen.1005506.s004"], "stats"=>{"downloads"=>4, "page_views"=>5, "likes"=>0}, "figshare_url"=>"https://figshare.com/articles/_Identification_of_Four_Mouse_Diabetes_Candidate_Genes_Altering_946_Cell_Proliferation_/1537237", "title"=>"Identification of Four Mouse Diabetes Candidate Genes Altering β-Cell Proliferation", "pos_in_sequence"=>0, "defined_type"=>4, "published_date"=>"2015-09-08 03:19:38"}
  • {"files"=>["https://ndownloader.figshare.com/files/2255168"], "description"=>"<p>Shown are the chromosomal localization, the log2 FC, the P-value and the accession numbers as RefSeq ID. Genes in bold are exclusively expressed either in NZO or B6-ob/ob islets (<15% rest mRNA).</p>", "links"=>[], "tags"=>["adaptive islet hyperplasia", "Ifi 202b Adenoviral overexpression", "NZO islets", "B 6", "57BL", "Mouse models", "Insulin resistance", "Pcp 4l", "Ifi 202b", "qtl", "genes differentially", "islet cells"], "article_id"=>1537236, "categories"=>["Uncategorised"], "users"=>["Oliver Kluth", "Daniela Matzke", "Anne Kamitz", "Markus Jähnert", "Heike Vogel", "Stephan Scherneck", "Matthias Schulze", "Harald Staiger", "Fausto Machicao", "Hans-Ulrich Häring", "Hans-Georg Joost", "Annette Schürmann"], "doi"=>"https://dx.doi.org/10.1371/journal.pgen.1005506.t002", "stats"=>{"downloads"=>1, "page_views"=>12, "likes"=>0}, "figshare_url"=>"https://figshare.com/articles/_Differentially_expressed_islet_genes_in_B6_ob_ob_and_NZO_located_in_a_QTL_Nob3_for_type_2_diabetes_related_traits_that_were_detected_by_linkage_studies_in_NZOxB6_F2_/1537236", "title"=>"Differentially expressed islet genes in B6-ob/ob and NZO located in a QTL (<i>Nob3</i>) for type 2 diabetes related traits that were detected by linkage studies in (NZOxB6) F2.", "pos_in_sequence"=>0, "defined_type"=>3, "published_date"=>"2015-09-08 03:19:38"}
  • {"files"=>["https://ndownloader.figshare.com/files/2255165"], "description"=>"<p>Effects of overexpression of indicated genes on BrdU incorporation in primary islet cells of B6 mice. Islets of B6 mice were isolated, dispersed and infected with adenoviruses encoding for the indicated genes. After infection, BrdU was applied for 72 h. For each candidate between 37,000 and 92,000 myc-expressing cells were evaluated. Due to variations in absolute primary islet cell proliferation depending on cell number and proper digestion, data are presented as fold change to control. Data are mean ± s.e.m. of 3–5 independent experiments **<i>P</i><0.01; ***<i>P</i><0.001.</p>", "links"=>[], "tags"=>["adaptive islet hyperplasia", "Ifi 202b Adenoviral overexpression", "NZO islets", "B 6", "57BL", "Mouse models", "Insulin resistance", "Pcp 4l", "Ifi 202b", "qtl", "genes differentially", "islet cells"], "article_id"=>1537233, "categories"=>["Uncategorised"], "users"=>["Oliver Kluth", "Daniela Matzke", "Anne Kamitz", "Markus Jähnert", "Heike Vogel", "Stephan Scherneck", "Matthias Schulze", "Harald Staiger", "Fausto Machicao", "Hans-Ulrich Häring", "Hans-Georg Joost", "Annette Schürmann"], "doi"=>"https://dx.doi.org/10.1371/journal.pgen.1005506.g005", "stats"=>{"downloads"=>1, "page_views"=>29, "likes"=>0}, "figshare_url"=>"https://figshare.com/articles/_Effects_of_Ifi202_Lefty1_Pcp4l1_Apoa2_Mndal_Slamf7_and_Pydc3_on_beta_cell_proliferation_/1537233", "title"=>"Effects of <i>Ifi202</i>, <i>Lefty1</i>, <i>Pcp4l1</i>, <i>Apoa2</i>, <i>Mndal</i>, <i>Slamf7</i>, and <i>Pydc3</i> on beta-cell proliferation.", "pos_in_sequence"=>0, "defined_type"=>1, "published_date"=>"2015-09-08 03:19:38"}
  • {"files"=>["https://ndownloader.figshare.com/files/2255163"], "description"=>"<p>Expression levels of the indicated 7 candidates localized within the diabesity-QTL <i>Nob3</i> on Chr. 1 in islets of NZO and B6-ob/ob mice as detected by RNAseq. Data represent mean ± s.e.m. of 3 animals. Statistics were calculated by edgeR and DEseq; ***<i>P</i><0.001.</p>", "links"=>[], "tags"=>["adaptive islet hyperplasia", "Ifi 202b Adenoviral overexpression", "NZO islets", "B 6", "57BL", "Mouse models", "Insulin resistance", "Pcp 4l", "Ifi 202b", "qtl", "genes differentially", "islet cells"], "article_id"=>1537231, "categories"=>["Uncategorised"], "users"=>["Oliver Kluth", "Daniela Matzke", "Anne Kamitz", "Markus Jähnert", "Heike Vogel", "Stephan Scherneck", "Matthias Schulze", "Harald Staiger", "Fausto Machicao", "Hans-Ulrich Häring", "Hans-Georg Joost", "Annette Schürmann"], "doi"=>"https://dx.doi.org/10.1371/journal.pgen.1005506.g003", "stats"=>{"downloads"=>1, "page_views"=>20, "likes"=>0}, "figshare_url"=>"https://figshare.com/articles/_Differentially_expressed_islet_genes_in_B6_ob_ob_and_NZO_located_in_a_QTL_for_type_2_diabetes_/1537231", "title"=>"Differentially expressed islet genes in B6-ob/ob and NZO located in a QTL for type 2 diabetes.", "pos_in_sequence"=>0, "defined_type"=>1, "published_date"=>"2015-09-08 03:19:38"}
  • {"files"=>["https://ndownloader.figshare.com/files/2255164"], "description"=>"<p>Representative immunocytochemical stainings of dispersed B6 islet cells infected with empty virus (AdØ) as control or adenoviruses expressing the designated genes followed by a 72 h BrdU labeling period. (a) Co-staining of insulin (Ins; green) and BrdU (magenta). White arrows indicate BrdU-positive beta-cells; white dashed arrow indicates BrdU-positive non-beta-cells. (b-i) Co-staining of the myc-tag of indicated proteins (b: control; c: <i>Lefty1</i>, d: <i>Ifi202b</i>, e: <i>ApoA2</i>; f: <i>Slamf7</i> g: <i>Mndal</i>; h: <i>Pcp4l1</i>; i: <i>Pydc3</i>; green) and BrdU (magenta). The infection rate was between 40 and 90%. Large nuclei are fibroblast-like cells that were left out in any morphometry (white F). Blue: DNA / nuclei. Scale bar: 50 μm.</p>", "links"=>[], "tags"=>["adaptive islet hyperplasia", "Ifi 202b Adenoviral overexpression", "NZO islets", "B 6", "57BL", "Mouse models", "Insulin resistance", "Pcp 4l", "Ifi 202b", "qtl", "genes differentially", "islet cells"], "article_id"=>1537232, "categories"=>["Uncategorised"], "users"=>["Oliver Kluth", "Daniela Matzke", "Anne Kamitz", "Markus Jähnert", "Heike Vogel", "Stephan Scherneck", "Matthias Schulze", "Harald Staiger", "Fausto Machicao", "Hans-Ulrich Häring", "Hans-Georg Joost", "Annette Schürmann"], "doi"=>"https://dx.doi.org/10.1371/journal.pgen.1005506.g004", "stats"=>{"downloads"=>1, "page_views"=>17, "likes"=>0}, "figshare_url"=>"https://figshare.com/articles/_Detection_of_BrdU_positive_primary_islet_cells_overexpressing_candidate_genes_/1537232", "title"=>"Detection of BrdU positive primary islet cells overexpressing candidate genes.", "pos_in_sequence"=>0, "defined_type"=>1, "published_date"=>"2015-09-08 03:19:38"}
  • {"files"=>["https://ndownloader.figshare.com/files/2255162"], "description"=>"<p>Overview of results obtained by RNAseq-based transcriptome analysis. Transcriptome of islets from B6-ob/ob and NZO mice that were fed with a carbohydrate-free diet for approximately 15 weeks and subsequently with a carbohydrate-containing diet for 2 days was studied by RNAseq. Indicated are number of genes that are expressed in the islets, those that are differentially expressed (<i>P</i><0.05, log2 FC > │0.6│) and the quantity of transcripts that are enriched in the indicated pathway as detected by MetaCore.</p>", "links"=>[], "tags"=>["adaptive islet hyperplasia", "Ifi 202b Adenoviral overexpression", "NZO islets", "B 6", "57BL", "Mouse models", "Insulin resistance", "Pcp 4l", "Ifi 202b", "qtl", "genes differentially", "islet cells"], "article_id"=>1537230, "categories"=>["Uncategorised"], "users"=>["Oliver Kluth", "Daniela Matzke", "Anne Kamitz", "Markus Jähnert", "Heike Vogel", "Stephan Scherneck", "Matthias Schulze", "Harald Staiger", "Fausto Machicao", "Hans-Ulrich Häring", "Hans-Georg Joost", "Annette Schürmann"], "doi"=>"https://dx.doi.org/10.1371/journal.pgen.1005506.g002", "stats"=>{"downloads"=>3, "page_views"=>43, "likes"=>0}, "figshare_url"=>"https://figshare.com/articles/_Beta_cell_failure_in_NZO_mice_is_associated_with_a_modulation_of_cell_adhesion_whereas_B6_ob_ob_mice_are_protected_against_diabetes_due_to_an_induction_of_beta_cell_cycle_/1537230", "title"=>"Beta-cell failure in NZO mice is associated with a modulation of cell adhesion whereas B6-ob/ob mice are protected against diabetes due to an induction of beta-cell cycle.", "pos_in_sequence"=>0, "defined_type"=>1, "published_date"=>"2015-09-08 03:19:38"}
  • {"files"=>["https://ndownloader.figshare.com/files/2255167"], "description"=>"<p>Shown are clusters of the main pathways upregulated in either B6-ob/ob (upper table) or NZO (lower table) islets in combination with the respective genes to be affected and their false discovery rate (FDR).</p>", "links"=>[], "tags"=>["adaptive islet hyperplasia", "Ifi 202b Adenoviral overexpression", "NZO islets", "B 6", "57BL", "Mouse models", "Insulin resistance", "Pcp 4l", "Ifi 202b", "qtl", "genes differentially", "islet cells"], "article_id"=>1537235, "categories"=>["Uncategorised"], "users"=>["Oliver Kluth", "Daniela Matzke", "Anne Kamitz", "Markus Jähnert", "Heike Vogel", "Stephan Scherneck", "Matthias Schulze", "Harald Staiger", "Fausto Machicao", "Hans-Ulrich Häring", "Hans-Georg Joost", "Annette Schürmann"], "doi"=>"https://dx.doi.org/10.1371/journal.pgen.1005506.t001", "stats"=>{"downloads"=>4, "page_views"=>11, "likes"=>0}, "figshare_url"=>"https://figshare.com/articles/_Main_pathways_up_regulated_by_carbohydrate_feeding_in_B6_ob_ob_and_NZO_mice_as_revealed_by_MetaCore_enrichment_pathway_analysis_/1537235", "title"=>"Main pathways up-regulated by carbohydrate feeding in B6-ob/ob and NZO mice as revealed by MetaCore enrichment pathway analysis.", "pos_in_sequence"=>0, "defined_type"=>3, "published_date"=>"2015-09-08 03:19:38"}
  • {"files"=>["https://ndownloader.figshare.com/files/2255166"], "description"=>"<p>(A) Based on pathway analysis performed with differentially expressed genes detected by RNAseq of B6-ob/ob and NZO islets the Lefty/Nodal/Smad3 pathway appears to play a central role for the initiation of beta-cell proliferation in B6-ob/ob. Red arrows and lines indicate the regulation of signaling molecules in B6-ob/ob beta-cells in response to Lefty1. The presence of Lefty1 inhibits Nodal signaling via the ActRII/ALK4 receptor leading to a reduced activity of the anti-proliferative protein Smad3 and ultimately to an induction of proliferation via Cyclin A2 (Ccna2), Cdk2 and Cdk1. Proteins in grey indicate candidates that were not significantly different in the RNAseq analysis. Black arrows indicate the regulation (RNAseq) of additional molecules that could be involved in the pathway. (B) Expression of the indicated cell-cycle transcripts in islets of NZO and B6-ob/ob mice before and after feeding carbohydrates for 2 days as detected by qRT-PCR. Data are mean ± s.e.m. of 4–6 animals; *<i>P</i>≤0.05.</p>", "links"=>[], "tags"=>["adaptive islet hyperplasia", "Ifi 202b Adenoviral overexpression", "NZO islets", "B 6", "57BL", "Mouse models", "Insulin resistance", "Pcp 4l", "Ifi 202b", "qtl", "genes differentially", "islet cells"], "article_id"=>1537234, "categories"=>["Uncategorised"], "users"=>["Oliver Kluth", "Daniela Matzke", "Anne Kamitz", "Markus Jähnert", "Heike Vogel", "Stephan Scherneck", "Matthias Schulze", "Harald Staiger", "Fausto Machicao", "Hans-Ulrich Häring", "Hans-Georg Joost", "Annette Schürmann"], "doi"=>"https://dx.doi.org/10.1371/journal.pgen.1005506.g006", "stats"=>{"downloads"=>2, "page_views"=>15, "likes"=>0}, "figshare_url"=>"https://figshare.com/articles/_Schematic_representation_of_pathways_that_are_affected_in_B6_ob_ob_and_NZO_islets_/1537234", "title"=>"Schematic representation of pathways that are affected in B6-ob/ob and NZO islets.", "pos_in_sequence"=>0, "defined_type"=>1, "published_date"=>"2015-09-08 03:19:38"}

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{"start_date"=>"2015-01-01T00:00:00Z", "end_date"=>"2015-12-31T00:00:00Z", "subject_areas"=>[]}
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